1. Field of the Invention
The present invention relates to novel anti-inflammatory and antiallergic compounds of the glucocorticosteroid series, methods of preparing such compounds, pharmaceutical compositions comprising such a compound, combinations containing such a compound, and therapeutic uses of such a compound. More particularly, the present invention relates to glucocorticosteroids that are isoxazolidine derivatives.
2. Discussion of the Background
Corticosteroids are potent anti-inflammatory agents, able to decrease the number, activity and movement of inflammatory cells. Corticosteroids are commonly used to treat a wide range of chronic and acute inflammatory conditions including asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, rheumatoid arthritis, inflammatory bowel disease and autoimmune diseases. Corticosteroids mediate their effects through the glucocorticoid receptor (GR). The binding of corticosteroids to GR induces its nuclear translocation which, in turn, affects a number of downstream pathways via DNA-binding-dependent (e.g. transactivation) and -independent (e.g. transespression) mechanisms.
Corticosteroids for treating chronic inflammatory conditions in the lung such as asthma and COPD are currently administered through inhalation. One of the advantages of employing inhaled corticosteroids (ICS) is the possibility of delivering the drug directly at site of action, thereby limiting systemic side-effects, thus resulting in a more rapid clinical response and a higher therapeutic ratio.
Although ICS treatment can afford important benefits, especially in asthma, it is important to minimize ICS systemic exposure which leads to the occurrence and severity of unwanted side effects that may be associated with chronic administration. Moreover, the limited duration of action of ICS currently available in the clinical practice contributes to suboptimal management of the disease. While the inhaler technology is the key point to target the lung, the modulation of the substituents on the corticosteroids molecular scaffold is important for the optimization of pharmacokinetic and pharmacodynamic properties in order to decrease oral bioavailability, confine pharmacological activity only in the lung (prodrugs and soft drugs) and increase systemic clearance. Moreover, long lasting ICS activity in the lung is highly desirable as once daily administration of ICS would allow the reduction of the frequency of administration and, thus, substantially improve patient compliance and, as a result, disease management and control. In sum, there is a pressing medical need for developing ICS with improved pharmacokinetic and pharmacodynamic characteristics.
Glucocorticoids isoxazolidine derivatives are for instance described in WO 2006/005611, GB 1578446 and in “Synthesis and topical anti-inflammatory activity of some steroidal [16α,17α-d] isoxazolidines” (J. Med. Chem., 25, 1492-1495, 1982), all of which are incorporated herein by reference in their entireties. Some glucocorticoid isoxazolidine derivatives are also described in the co-pending patent applications WO 2011/029547, WO 2012/123482, and WO 2012/123493, all of which are incorporated herein by reference in their entireties.
However, there remains a need for glucocorticosteroid with improved pharmacological properties.